The marked increase in the prevalence of obesity in the Untied States over the past decade poses a serious thereat to public health. Although the circulating adiposity signals leptin and insulin can reduce food intake and body weights in animal models, obese animals and humans exhibit high levels of food intake despite elevated plasma concentrations of insulin and leptin, indicating hypothalamic resistance to these despite elevated plasma concentrations of insulin and leptin, indicating hypothalamic resistance to these factors. Our research seeks to determine the importance of the PI3K pathway to insulin and leptin signaling in crucial neuronal subgroups within the hypothalamus. We propose to identity the expression pattern of PI3K within the hypothalamus using double-labeled I3HH and IHC for NPY, POMC, and the PI3K subunits p85 and p110. We also propose to use double-labeled IHC to identify neuronal populations in which P13K activity occurs in response to insulin and leptin treatment. Finally, we will develop mice with deletions of p85 targeted to POMC and NPY neurons to determine the importance of PI3K signaling in these pathways to the regulation of body weight. Insight into this shared intracellular pathway will allow progress toward treatment of impaired leptin and insulin regulation of body weight in the obese.